Alkamine sulfides of quinoline and method of producing the same



Patented Apr. 25", 1950 ALKAMINE SULFIDES F QUINOLINE AND METHOD OF PRODUCING THE SAME Raymond 0. Clinton and ChesterMerle Suter, Albany, N. Y., assignors to Sterling Drug Inc., Wilmington, Del., a corporation of Delaware NoDrawing. Application August 8, 1947,

. Serial No. 767,650

, 16 Claims. (01.260-288) .This invention relates to alkamine sulfides of ,quinoline and to a process of preparing such sulfides. or 4-(substituted-aminoalkylmercapto) More specifically. said sulfides are 2- quinolines.

such groups as lower alkyl, including methyl, H

ethyl, etc. and halogen, such as chloro, bromo, iodo, and fiuoro, as well as by other groups inert to mild alkali, such as alkoxy, nitro, and so on. Examples of such quinolyl groups include: 7 chlorol-quinolyl, 2-quinolyl, 4-methyl-2-quinolyl, 3-methyl-7-chlorol-quinolyl, 3,8-dimethyl- 4-quinolyl, 6 methoxy 4 quinolyl, 8-nitro-4- 'quinolyl, 5,8-dichloro-4-quinolyl, 6,8-dibromo-4lquinolyl, 5,6 dichloro 4 quinolyl, 3-iodo-5- chlor0-4-quinolyl, 3-bromo-7-chloro-4-quin0lyl, 5,7-,dibromo-4-quinolyl, bromo 8 chloro-4.- quinolyl, B-bromo-8-iodo-4-quinolyl, and the like. In the above general formula, R is preferablya lower alkylene radical having from 2 1105 carbon atoms, and B is preferably an aliphatic-secondaryor -tertiary-amino group. Examples" of BR- include: Z-diethylaminoethyl, B-diethylaminopropyl, 3'-N-piperidylpropyl, 2-(2-methyl- N-piperidyDethyl, 2-N-morpholinylethyl, 4-diniethylaminobutyl, 5-diethylamino-2-Dentyl, 2 di-n-butylaminoethyl, 5'- (2-propylamino) pentyl, '3-(n-butyla'mino) -propyl, and the like. The compounds of our invention are prepared by reaction between an (aliphatically-substituted-amino)alkanethiol and a 2- or 4-chloroquinoline in the presence of an acid-binding agent. The thiols used as intermediates can be prepared by methods which have been previously described (Albertson and Clinton, J. Am. Chem. "Soc. 67, 1222 (1945); Clinton and Salvador, ibid. 68, 2076 (1946); Laskowski and Clinton, ibid, 69,

The basic sulfides of our invention have the .same therapeutic actions, whether employed as the free bases, which provide the active component, .or-and often more conveniently-as their salts with non-toxic inorganic or organic acids; so it will be understood that the free bases andtheir salts are equivalents with. respect to the instantinven t ion Amongthe acids which ina'y be empldyedto form the salts are hydro chloric, phosphoric, sulfuric, sulfamic, tartaric, citric, benzoic, and the like.

, Further, it is to be understood that, while the invention is described in the following examples with particular reference to specific embodiments, it is not limited thereto, but is rather defined by the appended claims.

Example 1 7 chloro 4 (2 diethylaminoethylmercapto) quinoZine.-To a warm solution of 1.75 g. of sodium in 50 ml. of absolute alcohol, contained in a 250 ml. three-neck flask equipped with a reflux condenser, mechanical stirrer and dropping funnel, 10.1 g. of 2-diethylaminoethanethiol are added in one portion. The solution is heated under reflux with stirring and there is added; drop-wise over a period of twenty minutes a solution of 15.0 g. of 4,7-dichloroquinoline in ml. of absolute alcohol. There is an almost im mediate precipitation of sodium chloride. The mixture is refluxed and stirred for an additional four hours and then filtered. After removal of the alcohol in vacuo, the residual orange-colored. oil is distilled in vacuo, the desired fraction boiling at -9 C. at 0.06 mm. Several crystallizations of the distillate from petroleum ether (B. P. 28-38 C.) at 4.0 C. gives pale yellow prisms of 7-chloro-4-(2-diethylaminoethylmercapto) quinoline, M. P. 15-6 C.

7 chloro l (2 diethylaminoethylmercapto)- quinoline diphosphate. which is prepared by mix-- ing a methanolic solution of the base with arr.

equimolecular amount of 85% phosphoric acid,. crystallizes from ethanol in rosettes of small white: prisms, M. P. 153.5-7.5 C.

Example 2 4 (2 d2ethyZaminoethz Zmercapto) 3,8 dimethyZquz'noZine.The reaction between the sodium salt of 2-diethylaminoethanethiol and 4- chloro-3,8-dimethylquinoline is carried out as described above in Example 1. The crude product,

after removal of the alcohol in vacuo, is dissolved with 35% sodium hydroxide solution, and the After theprecipitated oil extracted into ether. ethereal extract has been dried, the ether is removed in vacuo to yield an oil, which is difficultto purify by distillation because of its tendency todecompose on strong heating However, the

base is readily purified through its picrate, as-

Example 1 but using 2.3 g. of sodium in '75 ml. of

3 follows. The oily base is dissolved in alcohol and the solution is treated with somewhat more than two equivalents of picric acid in alcoholic solution. The resulting dipicrate of 4-(2-diethylaminoethylmercapto) 3,8 dimethylquinoline 5 crystallizes from glacial acetic acid-alcohol solution in long feathery canary-yellow needles, M. P. 17'7-9 C. The dipicrate is shaken well with a mixture of ethyl acetate and dilute (about 5- aqueous hydrochloric acid solution. The 1 acidic layer is separated and, treatedrwith a nmonium hydroxide to liberate; ,lo a quincline, which is taken up in an appropriate solvent, such as ethyl acetate, ether; jetc'. .Rernoyal'itof the solvent in vacuo yields the baseiwhich is 5 treated in acetone solutionwith'"an exc'ess "of ethereal anhydrous hydrogen chloride, 1,,5% by weight). Crystallization fromab'solute' alcoholethyl acetate-ether gives short, pale yellow'needles of 4-(2-diethylaminoethylmercaptifi -3,8 di- 2O methylquinoline dihydrochloride, M. P. 188-90 C.

r 2- (3 dietftylaminopropylmercapto) 4;- 1 n,et?yZ- qaz'nolin er-This preparation is carried out as in absolute alcohol, 1%137 g. of S-diethylaminopropanethiol, and 17.8 g. of 2-chloro-4gmethylquinoline in 100 ml. of absolute alcohol. The reaction mixture is refluxed for nine hours. After removal of the alcohol by distillation in vacuo, the residual oil is distilled in vacuo, collecting the fraction boiling 2.13.135-60 C. at 0.35 mm. Redistillati'on ofthis fraction at 169 C. at 0.4 mm. yields, as a yellow oil, 2-(3 diethylaminopropylmercapto)- zi-methylquinoline. m

The d'ihydr'ochloride is prepared by dissolving 10 g. of the above base in '75 ml. of acetone and adding thereto an excess of ethereal anhydrous hydrogen chloride (15%). The yellow oil which 40 results is triturated to yield'a solid, which, wcenrss; filtered, recrystaliized once from absolute alcoholacetone and then once from isopropanol, and "dried'at"65 C., melts, at 198-201 C. (witlrdecom- Table I. Salts'of these bases are given in Table Table, I

No Compound 13 p Pies sure C. IV 111.. 1 2-(2-Dieth laminoethylmercapto)quinoline 113 "0.05 2 2 (3 Diethylaminopropylmercapto) 4 methyl ouiuoline hi. lo!) 0.40 3 4 (2- Diethylaminoethylmereapto) -3,6-dimethylquiuolinelmfichill" 1.11. 150 0.34 4 7-Chloro-4-(3 (lieth aminopropylmerca ,uin

oline 140 0.04 5 7 Chlolo A oline 152 9.03

6 7-C'hloro-4-(4-Diethylaminobutylmercapto)-quinr oline; ;,1 .cl 146 0.02

7 7-T' loro i-(fi-diethylo' 'ino 2 entylmerca t II 0 176 0.747 9 '7- Chlcro-4- (5- (2-propylamino)pentylmcrcapto) quinoline 1 The various salts corresponding to the bases givenin Table I arepr esente'cl below in TableII'.

Table II [Salts, M. P. 0.

, .Witli decomposition.

In addition, the following compounds result whentheabove directions ar followed but using thie appropriate 2- or 4-chlo-roquinolines and I ftaliphatically-substituted) -aminoalkylamine: 4- kdirnethylaminobufylmercapto)-5,8 dichloroquinoline, l- (2- (Z-meth yl-N-piperidyl) ethylmer- "l ne, 4 -(3fn-butylaininopropylmercapto)'-3iodoe "5-chlor'o'quinoline, 4- (2-N-mo;'pholinylethylmcrcapto') -3-'bromo-7-chloroquinoline, 4-"(3-diethylaminoprc-pyimercapto) -5,'7-dibrornoquinolinejv '6- nanny 2 (3-diethylaminoprop3 lm'ercapto qu'inolinej '7Ch10lf0-'-2(g-N-piperidylethyl pto') quinoline, 4-methyl-2- (2-n propylarninoethylmercapto)quinoline, and the like. We claim: 1

LTIJA compound from the group consisting of ho hav n the formula Q S-R- B m which Qis'a 'quinoline nucleus attached to S at one of the positions'12 and 4, R is a lower alkylfene radical having 2-5 carbon atoms, andB isia 'niember of the group consisting of alkylarnin'o,

'dialky arn o; morpholinyl, pip i and lk p iperidytradicals wherein the group Bis attached to B through the nitrogen atorn there'of "and acid addition salts thereof.

"2. A compound from the group consisting of tl'i'ose'having the general formula,

whereinQ is a quinoline nucleus attachedtos ,atthe 4-po'sition andR. is a lower 'alkyle'ne'rad- 'ical having 2-5 carbon atoms and aidadditibn "salts thereof.

3. A compound from the group consisting of those having the general formula,

wherein Q is a quinoline nucleus attached to -S at the 4-position and R is a lower alkylene radthose having the general formula,

wherein Q is a quinoline nucleus attached toS at t 4-position, R is a lower alkylene radical hav- 2-5 carbon atoms and NC5H1O .is an. N51 1- p eridyl radical and acid addition salts thereof. 5.Acompound from the group consistingof 7 7 chloro l -(2 diethylaminoethylmercaptolquinoline and acid addition salts thereof.

"* 61"A compound from the group consisting of 7 -"chl oro "-'4*-( 3 N piperidylpropylmercapto) quinoline and acid addition salts thereof.

'7. A compound from the group consisting of '7 "-'chloro 4 (5 (2 propylamino)pentylmercaptomuinoline and acid addition salts thereof.

"A compou'ndfrom the group consisting of 7 chloro 4 diethylamino 2 -pentylmer capto)quinoline and acid addition salts thereof.

9. A compound from the group consisting of 7 chloro 4 -(4 diethylaminobutylmercapto) quinoline and acid addition salts thereof.

10. A method of preparing a quinolyl alkamine sulfide having the general formula, Q-S-R-B, wherein Q is a quinoline nucleus attached to S at one of the positions two and four, R is a lower alkylene radical having 2-5 carbon atoms, and B is a member of the group consisting of alkylamino, dialkylamino, morpholinyl, piperidyl and alkylpiperidyl radicals wherein the group B is attached to R through the nitrogen atom thereof, which comprises reacting a chloroquinoline wherein the chlorine atom is at one of the positions two and four with an alkali metal salt of a basic thiol of the formula, B-RSH, wherein B and R have the meanings already given.

11. A method of preparing a quinolyl alkamine sulfide having the general formula,

wherein Q is a quinoline nucleus attached to S at one of the positions two and four and R is a lower alkylene radical having 2-5 carbon atoms, which comprises reacting a chloroquinoline wherein the chlorine atom is at one of the positions two and four with an alkali metal salt of a dialkylaminoalkanethiol of the formula,

wherein R is a lower alkylene radical.

12. A method of preparing '7-chloro-4-(5-diethylamino-2-pentylmercapto)quinoline which comprises reacting 4,7-dichloroquinoline with the sodium salt of 5-diethylamino-2-pentanethiol.

13. A method of preparing 7-chloro-4-(4-diethylaminobutylmercapto)quinoline which com- REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,572,768 Callsen Feb. 9, 1926 1,860,286 Hartmann et al. May 24, 1932 2,189,717 Scott Feb. 6, 1940 FOREIGN PATENTS Number Country Date 363,690 Great Britain Feb. 5, 1932 OTHER REFERENCES Wiselogle: Survey of Antimalarial Drugs,

1941-1945 (J. W. Edwards, Ann Arbor, Mich., 1946), pages 1107 and 1108.

Karrer: Organic Chemistry (Nordemann Publishing Co., New York, 1938), pp. 103 and 107-109.

Massie: Iowa State College J. Sci, vol 21, pp. 41-45 (1946). 

1. A COMPOUND FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULA Q-S-R-B IN WHICH Q IS A QUINOLINE NUCLEUS ATTACHED TO S AT ONE OF THE POSITIONS 2 AND 4 IS A LOWER ALKYLENE RADICAL HAVING 2-5 CARBON ATOMS, AND B IS A MEMBER OF THE GROUP CONSISTING OF ALKYLAMINO, DIALKYLAMINO, MORPHOLINYL, PIPERIDYL AND ALKYLPIPERIDYL RADICALS WHEREIN THE GROUP B IS ATTACHED TO R THROUGH THE NITROGEN ATOM THEREOF AND ACID ADDITION SALTS THEREOF. 